Overnutrition has been consistently identified as a serious health risk by several nutrition/health policy groups including the Food and Nutrition Board of the National Academy of Science, the U. S. Senate Select Committee on Nutrition and Human Needs (Dietary Goals for the United States) and the USDA and DHEW (Nutrition and Your Health: Dietary Guidelines for Americans). The high rate of failure to maintain energy balance has been related to the lack of understanding of the endogenous mechanisms for long-term regulation. Central mechanisms for the control of food intake and the regulation of energy balance are the focus of this proposal. Our main hypothesis is that metabolic activity within specific areas of the brain may be altered to mimic peripheral energy status. In turn these brain areas may utilize this metabolic information to regulate energy balance through control of food intake, endocrine status and autonomic activity. To test this hypothesis, three series of experiments are described. The first series test the main hypothesis directly. The mechanisms of translation of metabolic signals to neurochemical signals is the subject of the second series of experiments. Finally, intervention experiments which test the proposed mechanism are the subject of the third series of experiments. The objectives of the proposal are as follows: 1) To test the hypothesis by directly manipulating hypothalamic metabolic activity and measuring changes in food intake and body composition, 2) To determine the mechanisms by which food intake, energy expenditure or body composition were altered, in situ hybridization measures of neuropeptide mRNA will be made and in vitro release of neuropeptides and neurotransmitters will be measured. The neuropeptides and neurotransmitters known to alter feeding behavior and body composition will be studied, and 3) To determine the mechanisms by which CNS metabolism directly influences the in vitro release of neuropeptides and neurotransmitters. An in vivo approach will be used to validate the in vitro results. Two main approaches will be utilized, antisense- oligonucleotide and the use of specific antibodies. These studies should provide a basic understanding of energy balance regulation and provide the tools for controlling some forms of obesity.